Fighting Cancer, Aging at DNA Level

Fighting Cancer, Aging at DNA Level

When most of us think of treating cancer, we focus on surgery or chemotherapy to shrink or remove tumors. But a researcher and undergraduate student at the College of Medicine’s Burnett School of Biomedical Sciences are looking to erase cancer at the epigenetic level, by studying how the body turns on and off certain genes in response to environmental factors like toxins, cigarette smoke or excessive sunlight.

Dr. Mark Muller, a cancer researcher, and Jeremy Tran, a junior biomedical sciences major, recently published a paper in the January edition of the journal ChemMedChem. In it, they reported that an existing FDA-approved drug that is currently used to treat inflammatory colon disease appears to halt this “turn-off” function of genes that may cause serious health consequences like cancer.

The issue involved in the research is the delicate balance between growth, repair and death that cells must keep in order to sustain life. Cells must grow and repair themselves to replenish but must ensure that their growth doesn’t become uncontrolled, which is the very nature of cancer.

Part of the cell’s survival mechanism is methylation, a process where chemicals called “methyl groups” get added to cellular DNA to keep it in good repair. But in this repair process, scientists have discovered that methylation can turn off the functions of some genes. The genes don’t change, only their behavior does. And if their specific behavior is to act as a tumor suppressor, for example, and that function is silenced, the body has reduced abilities to fight tumors. Thus, in trying to repair one problem, the body may be causing another.

In conjunction with researchers from the Mayo Clinic and Universidad Nacional Autonoma de Mexico, Dr. Muller’s team created DNA damage and repair in the lab. Researchers cut a human DNA helix and watched the ensuing repair and DNA methylation. They could see such microscopic changes by using a chemical derived from jellyfish that makes the sea creatures glow in different colors. The glowing cells were analyzed to see how repaired genes reproduced. Did silenced genes stay silent or did they gain back their behavior function in future generations as they divided and grew? The team discovered that the offspring of the repaired genes stayed silent and that such replication of altered genes can lead to a loss of growth control, or possibly cancer.

In an attempt to de-silence the gene, Dr. Muller’s team examined a database of 1,552 FDA-approved drugs to see if any impacted this genetic turn-off function. They found only one drug, Olsalazine that is currently approved to treat Crohn’s disease that unsilenced the gene’s behavior in subsequent generations of cell growth. In Crohn’s patients, Olsalazine reduces the debilitating inflammation of the chronic colon disease. At the DNA level, it appears to “fix” genetic silencing without the severe toxicity that current epigenetic treatments bring. Because the drug is already FDA approved, getting it into further studies will be easier and less costly than trying to create a new epigenetic pharmaceutical from scratch.  Moreover, finding new mechanisms with existing, FDA approved drugs is extremely valuable information from a clinical perspective.

“We are employing a system that tests for the action of the drug in the context of the living cell” said Dr. Muller. “Such a cell-based screen could allow us to find the next epigenetic drug.”  Dr. Muller also noted that there is a pressing need for new blockbuster epi-therapuetics, “but few candidates are in the pipeline”.

Tran said he was driven to epigenetic research because it involves traits that are heritable. Identical twins, with the same genome, can have dramatically different health and disease states because of epigenetics – the body’s ability to turn on or off gene behaviors based on environmental factors. “Epigenetics shows that your actions – the fatty foods you eat, how much you exercise, whether you smoke – have an impact on genetics,” said the student, who won first place in the Life Sciences 3 category at UCF’s recent Showcase of Undergraduate Research Excellence.

Tran hopes to pursue an M.D.-Ph.D. degree because he wants to be a physician who is on the cutting edge of research. “Being a physician and a scientist allows me to pursue the best of both worlds,” he said. “Both fields help people out. By doing research myself for my patients, I cut out the middle man.”

The next step in UCF’s epigenetic research is understanding how Olsalazine actually impacts epigenetic silencing.  What pathways does it use and what is the precise mechanism of action? The scientists also have to determine dosages – what dosage is safe yet still does the job vs. what is a highly toxic or lethal dose? The goal, say the UCF researchers, is to develop a cancer preventative and therapeutic drug that patients could take regularly to prevent dangerous gene silencing without the harsh system-wide damage caused by most chemotherapy drugs.

It is also possible that epi-therapeutics have value as anti-aging compounds.  This idea is currently being tested in collaboration with other UCF researchers including Dr. Michal Masternak who is studying aging using a novel ‘longevity’ mouse model created by changing the animal’s genome.  These transgenic mice live longer than normal mice and Dr. Muller and collaborators believe epigenetics may be involved. This research provides a unique opportunity to examine maintenance defects in the human ‘epigenome’ as we age.